Department of Medicine, Division of Endocrinology and Metabolism, Indiana University School of Medicine, 541 North Clinical Drive, CL 459, Indianapolis, Indiana 46202, USA.
Endocrinology. 2011 Dec;152(12):4504-13. doi: 10.1210/en.2011-1137. Epub 2011 Oct 18.
Mutations in the GALNT3 gene cause tumoral calcinosis characterized by ectopic calcifications due to persistent hyperphosphatemia. We recently developed Galnt3 knockout mice in a mixed background, which had hyperphosphatemia with increased bone mineral density (BMD) and infertility in males. To test the effect of dietary phosphate intake on their phenotype, Galnt3 knockout mice were generated in the C57BL/6J strain and fed various phosphate diets: 0.1% (low), 0.3% (low normal), 0.6% (normal), and 1.65% (high). Sera were analyzed for calcium, phosphorus, alkaline phosphatase, creatinine, blood urine nitrogen, 1,25-dihydroxyvitamin D, osteocalcin, tartrate-resistant acid phosphatase 5b, and fibroblast growth factor 23 (Fgf23). Femurs were evaluated by dual-energy x-ray absorptiometry, dynamic histomorphometry, and/or microcomputed tomography. Galnt3 knockout mice in C57BL/6J had the same biochemical phenotype observed in our previous study: hyperphosphatemia, inappropriately normal 1,25-dihydroxyvitamin D level, decreased alkaline phosphatase activity, and low intact Fgf23 concentration but high Fgf23 fragments. Skeletal analyses of their femurs revealed significantly high BMD with increased cortical bone area and trabecular bone volume. On all four phosphate diets, Galnt3 knockout mice had consistently higher phosphorus levels and lower alkaline phosphatase and intact Fgf23 concentrations than littermate controls. The low-phosphate diet normalized serum phosphorus, alkaline phosphatase, and areal BMD but failed to correct male infertility in Galnt3 knockout mice. The high-phosphate diet did not increase serum phosphorus concentration in either mutant or control mice due to a compensatory increase in circulating intact Fgf23 levels. In conclusion, dietary phosphate restriction normalizes biochemical and skeletal phenotypes of Galnt3 knockout mice and, thus, can be an effective therapy for tumoral calcinosis.
GALNT3 基因突变导致肿瘤性钙化,其特征为持续性高磷血症引起的异位钙化。我们最近在混合背景下开发了 Galnt3 基因敲除小鼠,这些小鼠表现为高磷血症伴骨矿物质密度(BMD)增加和雄性不育。为了测试饮食磷酸盐摄入对其表型的影响,我们在 C57BL/6J 品系中生成了 Galnt3 基因敲除小鼠,并给它们喂食不同的磷酸盐饮食:0.1%(低)、0.3%(低正常)、0.6%(正常)和 1.65%(高)。分析血清中的钙、磷、碱性磷酸酶、肌酐、血尿素氮、1,25-二羟维生素 D、骨钙素、抗酒石酸酸性磷酸酶 5b 和成纤维细胞生长因子 23(Fgf23)。通过双能 X 射线吸收仪、动态组织形态计量学和/或微计算机断层扫描评估股骨。C57BL/6J 中的 Galnt3 基因敲除小鼠具有我们之前研究中观察到的相同生化表型:高磷血症、不适当的正常 1,25-二羟维生素 D 水平、碱性磷酸酶活性降低以及完整的 Fgf23 浓度低但 Fgf23 片段高。股骨的骨骼分析显示,BMD 显著升高,皮质骨面积和小梁骨体积增加。在所有四种磷酸盐饮食中,Galnt3 基因敲除小鼠的磷水平始终较高,碱性磷酸酶和完整的 Fgf23 浓度较低,而与其同窝对照相比。低磷饮食可使血清磷、碱性磷酸酶和面积 BMD 正常化,但不能纠正 Galnt3 基因敲除小鼠的雄性不育。高磷饮食不会增加突变或对照小鼠的血清磷浓度,因为循环中完整的 Fgf23 水平代偿性增加。总之,饮食磷酸盐限制可使 Galnt3 基因敲除小鼠的生化和骨骼表型正常化,因此可作为肿瘤性钙化的有效治疗方法。